We seek to understand how the bioavailability of TGF-beta, which is important in physiological and pathological processes, such as cancer, fibrosis, and autoimmune diseases, is regulated. TGF-beta is released as an inactive complex. The complex consists of TGF-beta, the TGF-beta propeptide and a second gene product, the latent TGF-beta binding protein (LTBP). Null or hypomorphic mutations of the LTBP genes (Ltbp-1L, 3, and 4) produce limited, distinct abnormalities suggesting that LTBP-dependent pathologies appear only in tissues in which redundant LTBP isoforms are absent. However, cells and tissues produce multiple LTBPs suggesting LTBPs have non-redundant functions. Also, Ltbp-3-/- or Ltbp-4-/- lung cells have cell autonomous TGF-beta-dependent phenotypes reversed only by expression of the missing LTBP, indicating a requirement for specific LTBP isoforms. To address this apparent contradiction, we hypothesize that LTBP isoforms localize latent TGF-beta to unique environments specific for individual activation mechanisms and that this specificity contributes to the diversity of latent TGF-beta activation and action. We will examine LTBP isoform function in vitro and in vivo.
In Aim 1, we will isolate lung cell lines from Ltbp null mice, transfect the cells lines with Ltbp-1, -3, -4 or chimeric Ltbp expression vectors to ascertain the Ltbp structural requirements for phenotype rescue. This approach will clarify whether one LTBP can substitute for another and will identify individual LTBP domains that generate diversity.
In Aim 2, we will analyze the expression pattern of Ltbp-1 L, 3, and 4 in the lung to test whether null phenotypes reflect Ltbp expression patterns or another parameter, such as matrix localization or TGF-beta activation. As a further test of uniqueness or redundancy, we will generate compound double Ltbp null mice and determine if either novel phenotypes appear or the phenotypes are additive. Finally, we will generate mice in which the Ltbp-1 or Ltbp-4 cDNA is knocked into the mutant Ltbp-3 gene. The ability of the """"""""knockin"""""""" Ltbp to replace the deleted Ltbp, as monitored by tissue (lung) phenotypes, will demonstrate uniqueness and redundancy. These experiments will clarify the role of the LTBPs in directing latent TGF-beta to distinct extracellular locations that determine unique functions. This information may yield understanding concerning TGF-beta- dependent lung pathologies and suggest ways to control these adverse events in a tissue-specific manner.
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| Rifkin, Daniel B; Rifkin, William J; Zilberberg, Lior (2018) LTBPs in biology and medicine: LTBP diseases. Matrix Biol 71-72:90-99 |
| Morkmued, Supawich; Hemmerle, Joseph; Mathieu, Eric et al. (2017) Enamel and dental anomalies in latent-transforming growth factor beta-binding protein 3 mutant mice. Eur J Oral Sci 125:8-17 |
| Recouvreux, M Victoria; Camilletti, M Andrea; Rifkin, Daniel B et al. (2016) The pituitary TGF?1 system as a novel target for the treatment of resistant prolactinomas. J Endocrinol 228:R73-83 |
| Robertson, Ian B; Rifkin, Daniel B (2016) Regulation of the Bioavailability of TGF-? and TGF-?-Related Proteins. Cold Spring Harb Perspect Biol 8: |
| Zilberberg, Lior; Phoon, Colin K L; Robertson, Ian et al. (2015) Genetic analysis of the contribution of LTBP-3 to thoracic aneurysm in Marfan syndrome. Proc Natl Acad Sci U S A 112:14012-7 |
| Robertson, Ian B; Horiguchi, Masahito; Zilberberg, Lior et al. (2015) Latent TGF-?-binding proteins. Matrix Biol 47:44-53 |
| Horiguchi, Masahito; Todorovic, Vesna; Hadjiolova, Krassimira et al. (2015) Abrogation of both short and long forms of latent transforming growth factor-? binding protein-1 causes defective cardiovascular development and is perinatally lethal. Matrix Biol 43:61-70 |
| Dabovic, Branka; Robertson, Ian B; Zilberberg, Lior et al. (2015) Function of latent TGF? binding protein 4 and fibulin 5 in elastogenesis and lung development. J Cell Physiol 230:226-36 |
| Rognoni, Emanuel; Widmaier, Moritz; Jakobson, Madis et al. (2014) Kindlin-1 controls Wnt and TGF-? availability to regulate cutaneous stem cell proliferation. Nat Med 20:350-9 |
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